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M608642200v1
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Papers In Press, published online ahead of print November 30, 2006
J. Biol. Chem, 10.1074/jbc.M608642200
Submitted on September 7, 2006
Revised on November 22, 2006
Accepted on November 30, 2006

Activation of SHP2 protein tyrosine phosphatase increases HoxA10-induced repression of the genes encoding gp91PHOX and p67PHOX

Stephan Lindsey, Weiqi Huang, Elizabeth Horvath, Chunliu Zhu, and Elizabeth A. Eklund

Medicine (Hematology/Oncology), Northwestern University Medical School and the Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois 60611

Corresponding Author: e-eklund{at}northwestern.edu

The CYBB and NCF2 genes encode the phagocyte oxidase proteins gp91PHOX and p67PHOX, respectively. These genes are transcribed after the promyelocyte stage of differentiation and transcription continues until cell death. In undifferentiated myeloid cells, homologous cis elements in the CYBB and NCF2 genes are repressed by the homeodomain transcription factor HoxA10. During cytokine-induced myelopoiesis, tyrosine phosphorylation of HoxA10 decreases binding affinity for the CYBB and NCF2 cis elements. This abrogates HoxA10-induced transcriptional repression as differentiation proceeds. Therefore, mechanisms involved in differentiation-stage-specific HoxA10-tyrosine-phosphorylation are of interest, since HoxA10-phosphorylation modulates myeloid specific gene transcription. In the current studies, we find that HoxA10 is a substrate for SHP2 protein tyrosine phosphatase in undifferentiated myeloid cells. In contrast, we find that HoxA10 is a substrate for a constitutively active, mutant form of SHP2 in both undifferentiated and differentiating myeloid cells. Expression of such SHP2-mutants results in persistent HoxA10-repression of CYBB and NCF2 transcription during myelopoiesis. HoxA10-overexpression and activating SHP2-mutations have both been described in human myeloid malignancies. Therefore, our results suggest these mutations could cooperate; leading to decreased myeloid gene transcription and functional differentiation block in myeloid cells with both defects.


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